Abstract
Malignant gliomas are currently treated with temozolomide (TMZ), but often exhibit resistance to this agent. CD133(+) cancer stem cells, a population believed to contribute to the tumor's chemoresistance, bear the activation of Notch and Sonic hedgehog (SHH) pathways. In this study, we examined whether inhibition of both pathways enhances the efficacy of TMZ monotherapy in the context of glioma stem cells. Transcriptional analysis of Notch and SHH pathways in CD133(+)-enriched glioma cell populations showed the activity of these pathways. CD133(+) cells were less susceptible to TMZ treatment than the unsorted glioma counterparts. Interestingly, Notch and SHH pathway transcriptional activity in CD133(+) glioma cells was further enhanced by TMZ exposure, which led to NOTCH 1, NCOR2, and GLI1 upregulation (6.64-, 3.73-, and 2.79-fold, respectively) and CFLAR downregulation (4.22-fold). The therapeutic effect of TMZ was enhanced by Notch and SHH pathway pharmacological antagonism with GSI-1 and cyclopamine. More importantly, simultaneous treatment involving TMZ with both of these compounds led to a significant increase in CD133(+) glioma cytotoxicity than treatment with any of these agents alone (P < 0.05). In conclusion, CD133(+) glioma cells overexpress genes involved in Notch and SHH pathways. These pathways contribute to the chemoresistant phenotype of CD133(+) glioma cells, as their antagonism leads to an additive effect when used in combination with TMZ.
Highlights
Despite the fact that temozolomide (TMZ) constitutes the standard of care for patients with malignant gliomas, these tumors are relatively resistant to chemotherapy [1,2]
As previously reported [30], our experiments showed that the population of CD133+ cells was a small fraction of the whole cell pool, with 0.02% in the U87MG cell line, and an average of 2.51% for the primary Glioblastoma Multiforme (GBM) specimens (Table 1)
We explored the transcriptional profile of CD133+-enriched glioma cells in the context of the Sonic hedgehog (SHH), Notch and Wnt-β-catenin pathways
Summary
Despite the fact that temozolomide (TMZ) constitutes the standard of care for patients with malignant gliomas, these tumors are relatively resistant to chemotherapy [1,2]. Several mechanisms are thought to account for such resistance, and DNA repair-related genes such as MGMT, MSH2, and MSH6 have been identified as key players involved in tumor survival after treatment with alkylating agents [1,3,4,5]. A small population of cells with self-renewal capacity and immature phenotype, called “glioma stem cells,” have been shown to be highly resistant to chemotherapy and radiation [6,7,8]. Several authors have hypothesized that these tumor stem cells are the source of the recurrent tumors after treatment. The phenotype, ex vivo assays and markers that define such stem cells are debated topics [6,7,8,9]. The CD133+ tumor cell population was enriched after radiation and exhibited an increase in DNA repair capacity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
